Tripathi Siddhant, Sharma Yashika, Kumar Dileep
Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India.
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
Protein Pept Lett. 2025;32(1):2-17. doi: 10.2174/0109298665348075241121071614.
Alzheimer's disease (AD) treatments currently available have ineffective results. Previously employed Acetylcholine esterase inhibitors and memantine, an NMDA receptor antagonist, target a single target structure that plays a complex role in the multifactorial progression of disease. Memantine moderates the toxic effects of excessive glutamate activity by blocking NMDA receptors, which decreases neurotoxicity in AD, while acetylcholine esterase inhibitors function by blocking cholinergic receptors (muscarinic and nicotinic), preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission, thus improving cognitive functions in mild to moderate stages of AD. Every drug class targets a distinct facet of the intricate pathophysiology of AD, indicating the diverse strategy required to counteract the advancement of this neurodegenerative disorder. Thus, patients are currently not getting much benefit from current drugs. A closer look at the course of AD revealed several potential target structures for future drug discovery. AD drug development strategies focus on developing new target structures in addition to well-established ones for combination treatment regimens, ideally with a single drug that can target two different target structures. Because of their roles in AD progression pathways like pathologic tau protein phosphorylations as well as amyloid β toxicity, protein kinases have been identified as potential targets. This review will give a quick rundown of the first inhibitors of single protein kinases, such as glycogen synthase kinase (gsk3) β, along with cyclin-dependent kinase 5. We will also look into novel inhibitors that target recently identified protein kinases in Alzheimer's disease, such as dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Additionally, multitargeting inhibitors, which target multiple protein kinases as well as those thought to be involved in other processes related to AD will be discussed. This kind of multitargeting offers prospective hope for improved patient outcomes down the road since it is the most effective way to impede multifactorial disease development.
目前可用的阿尔茨海默病（AD）治疗方法效果不佳。以前使用的乙酰胆碱酯酶抑制剂和美金刚（一种NMDA受体拮抗剂），靶向单一靶点结构，该结构在疾病的多因素进展中发挥着复杂作用。美金刚通过阻断NMDA受体来减轻谷氨酸过度活动的毒性作用，从而降低AD中的神经毒性，而乙酰胆碱酯酶抑制剂则通过阻断胆碱能受体（毒蕈碱型和烟碱型）发挥作用，防止乙酰胆碱分解，从而增强胆碱能传递，进而改善AD轻度至中度阶段的认知功能。每一类药物都针对AD复杂病理生理学的一个不同方面，这表明需要采取不同的策略来对抗这种神经退行性疾病的进展。因此，目前患者从现有药物中获益不多。对AD病程的深入研究揭示了几个未来药物研发的潜在靶点结构。AD药物研发策略除了关注已确立的靶点结构用于联合治疗方案外，还侧重于开发新的靶点结构，理想情况下是一种能够靶向两种不同靶点结构的单一药物。由于蛋白激酶在AD进展途径如病理性tau蛋白磷酸化以及淀粉样β毒性中发挥作用，它们已被确定为潜在靶点。本综述将快速介绍单一蛋白激酶的首批抑制剂，如糖原合酶激酶（GSK3）β以及细胞周期蛋白依赖性激酶5。我们还将研究针对AD中最近发现的蛋白激酶的新型抑制剂，如双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）。此外，还将讨论靶向多种蛋白激酶以及那些被认为与AD其他相关过程有关的多靶点抑制剂。这种多靶点策略为改善患者预后带来了前瞻性希望，因为它是阻碍多因素疾病发展的最有效方法。
